The invention relates to a process for the preparation of cis-6-hexadecenoic acid.
cis-6-Hexadecenoic acid (sapienic acid) is the most common unsaturated fatty acid present in human skin sebum. Because of its antimicrobial action, cis-6-hexadecenoic acid is a desired active ingredient for cosmetic and dermatological applications.
For the preparation of cis-6-hexadecenoic acid and esters thereof, microbiological and also chemical processes are known.
For example, WO 96/13591 describes the stereoselective elimination of hydrogen from palmityl esters by means of microorganisms.
A chemical synthesis route for obtaining cis-6-hexadecenoic acid is described in WO 98/16104. However, the multistage synthesis produces only small yields and, moreover, uses reagents which are questionable with regard to safety, such as, for example, liquid ammonia and potassium cyanide.
It is an object of the present invention to provide a novel process for the preparation of cis-6-hexadecenoic acid which proceeds with a high Z/E selectivity and does not have the disadvantages of the hitherto known processes with regard to safety.
We have found that this object is achieved by a process for the preparation of cis-6-hexadecenoic acid of the formula I 
which comprises reacting
a1) a triphenylphosphonium salt of the formula II,
R1OOCxe2x80x94(CH2)5xe2x80x94P(R2)3+Xxe2x88x92xe2x80x83xe2x80x83II
xe2x80x83in which the substituents, independently of one another, have the following meanings:
R1 is C1-C12-alkyl, aryl;
R2 is aryl and
Xxe2x88x92 is an anion equivalent of an inorganic or organic acid with decanal of the formula III
H3Cxe2x80x94(CH2)8xe2x80x94CHxe2x95x90Oxe2x80x83xe2x80x83III
xe2x80x83in a Wittig reaction, or reacting
a2) a triphenylphosphonium salt of the formula IV,
H3Cxe2x80x94(CH2)9xe2x80x94P(R2)3+Xxe2x88x92xe2x80x83xe2x80x83IV
xe2x80x83in which the substituents R2 and Xxe2x88x92, independently of one another, have the meanings given above:
with an aldehyde of the formula V,
R1OOCxe2x80x94(CH2)4xe2x80x94CHxe2x95x90Oxe2x80x83xe2x80x83V
in which R1 has the meaning given above,
in a Wittig reaction
and
b) saponifying the ester, formed by process step a1) or a2), of the formula VI, 
xe2x80x83in which R1 has the meaning given above.
Alkyl radicals for R1 which may be mentioned are branched or unbranched C1-C12-alkyl chains, such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Preferred alkyl radicals are C1-C4-alkyl groups, particularly preferably methyl, ethyl, n-propyl and 1-methylethyl, very particularly preferably methyl and ethyl.
Aryl for R1 is to be understood as meaning aromatic rings or ring systems having 6 to 18 carbon atoms in the ring system, for example phenyl or naphthyl, which may optionally be substituted by one or more radicals such as halogen, e.g. fluorine, chlorine or bromine, cyano, nitro, amino, C1-C4-alkylamino, C1-C4-dialkylamino, hydroxyl, C1-C4-alkyl, C1-C4-alkoxy or other radicals. Preference is given to phenyl, methoxyphenyl and naphthyl.
The term aryl for R2 refers to customary aryl radicals occurring in phosphines and phosphonium salts, such as phenyl, toluene, naphthyl, in each case optionally substituted, preferably phenyl.
The radical Xxe2x88x92 is an anion equivalent of an inorganic or organic acid, preferably a strong inorganic or organic acid.
The expression strong acid includes hydrohalic acids (in particular hydrochloric acid and hydrobromic acid), sulfuric acid, phosphoric acid, sulfonic acids and other inorganic or organic acids with a comparable degree of dissociation. Strong organic acids in this connection are also to be understood as meaning C1-C6-alkanoic acids.
Particularly preference is given to anions of such acids, chosen from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid and sulfonic acid. Very particular preference is given to Clxe2x88x92, Brxe2x88x92, CnH2n+1xe2x80x94SO3xe2x88x92 (where n=1-4), Phxe2x80x94SO3xe2x88x92, p-Tolxe2x80x94SO3xe2x88x92 or CF3xe2x80x94SO3xe2x88x92,
The invention provides, in particular, a process for the preparation of cis-6-hexadecenoic acid wherein, in process step a), a triphenylphosphonium salt of the formula II is reacted with decanal of the formula III.
A further preferred embodiment of the process involves using a triphenylphosphonium salt of the formula IIa,
R1OOCxe2x80x94(CH2)4xe2x80x94P(Ph)3+Xxe2x88x92xe2x80x83xe2x80x83IIa
in which the substituents, independently of one another, have the following meanings:
R1 is C1-C4-alkyl, in particular methyl, ethyl, n-propyl and 1-methylethyl;
Ph is phenyl;
Xxe2x88x92 is an anion equivalent of a strong inorganic or organic acid, in particular Clxe2x88x92, Brxe2x88x92, CnH2n+1xe2x80x94SO3xe2x88x92 where n=1-4, Phxe2x80x94SO3xe2x88x92, p-Tolxe2x80x94SO3xe2x88x92 or CF3xe2x80x94SO3xe2x88x92.
The reaction of the phosphonium salts II to IV to give the cis-6-hexadecenoic esters of the formula VI can take place under the conditions customary for Wittig reactions.
The reaction in step a) usually takes place in temperatures between xe2x88x9230xc2x0 C. and +50xc2x0 C., preferably between xe2x88x9210 and +30xc2x0 C., particularly preferably between +10xc2x0 C. and +25xc2x0 C.
In this connection, it is possible either to initially introduce both starting compounds (phosphonium salt and aldehyde) in the solvent and to add the base, or else to initially introduce a solution of the phosphonium salt, to add the base and only then to add a solution of the aldehyde.
Bases which can be used are all bases customary for Wittig condensations, e.g. alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal hydrides, such as sodium hydride or potassium hydride.
Also suitable as bases are organolithium compounds, such as, for example, n-butyllithium, tert-butyllithium, phenyllithium or alkali metal amides, such as lithium amide, potassium amide or sodium amide, lithium diisopropylamide and also alkali metal hexamethyldisilazides. Preferred bases used for the Wittig reaction according to the invention are sodium or potassium hexamethyldisilazide, and potassium amide or sodium amide.
The amount of base used is usually in the range from 0.8 to 5 mol, preferably 1 to 3 mol per mole of the phosphonium salt II or IV used.
Suitable solvents for the process step a) are, inter alia, aromatic hydrocarbons, such as toluene, xylene or benzene, cyclic or open-chain ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane or THF, and DMF or DMSO. Preferred solvents are toluene, THF and/or DMSO.
When conversion is complete, the reaction mixture is hydrolyzed, and the ester formed is removed from the aqueous solution by extraction.
The extractants used are advantageously hexane, heptane or ethyl acetate. It is, however, also possible to use all other water-immiscible organic solvents, such as ethers, aliphatic hydrocarbons, halogenated and aromatic hydrocarbons, for the extraction.
The solvents, in particular the DMF or DMSO, remain largely in the aqueous phase during this extraction and also retain the triphenylphosphine oxide, formed in the Wittig reaction, largely in the aqueous phase.
The process according to the invention is notable for the fact that the Wittig reaction in process step a) takes place with a Z/E selectivity greater than 90/10, preferably with a Z/E selectivity between 92/8 and 99/1, particularly preferably between 94/6 and 97/3.
The saponification in process step b) is usually carried out by initially introducing the cis-6-hexadecenoic ester in a C1-C6-alcohol, preferably ethanol, n-propanol, isopropanol or butanol, particularly preferably in ethanol, and adding a base, for example an aqueous or aqueous-alcoholic solution of an alkali metal or alkaline earth metal hydroxide, preferably an aqueous-ethanolic sodium hydroxide solution or potassium hydroxide solution.
The reaction temperatures in stage b) are in the range between 0xc2x0 C. and the boiling temperature of the solvent, preferably between 10xc2x0 C. and 100xc2x0 C., particularly preferably in the range between 30xc2x0 C. and 80xc2x0 C.
The amount of catalyst used for the saponification of the ester is in the range between 0.01 and 5 mol %, preferably between 0.02 and 1 mol %, based on the starting material VI.
By reference to the examples below, the process according to the invention will be explained in more detail.